Kroenke Mark A, Weeraratne Dohan K, Deng Hongjie, Sloey Bethlyn, Subramanian Raju, Wu Benjamin, Serenko Michael, Hock M Benjamin
Amgen Inc., Medical Sciences, Thousand Oaks, CA, United States.
Amgen Inc., Pharmacokinetics and Drug Metabolism, Thousand Oaks, CA, United States.
J Immunol Methods. 2017 Jun;445:37-44. doi: 10.1016/j.jim.2017.03.005. Epub 2017 Mar 6.
The immunogenicity risk assessment and bioanalytical strategy for novel therapeutics should account for both unique biophysical properties and potential consequences of immunogenicity. When assessing the immunogenicity risk of etelcalcetide, a peptide agonist of the calcium-sensing receptor, we considered the potential that the d-amino acid 'backbone' and biotransformation of etelcalcetide could allow the drug to act as a hapten. As a consequence, we validated and implemented a surface plasmon resonance immunoassay platform with both etelcalcetide and etelcalcetide-'carrier' surfaces to detect anti-drug antibodies (ADA). No evidence of in-vitro neutralizing activity with surrogate controls was detected despite multiple immunization approaches and a sensitive cell-based activity assay. Therefore, a neutralizing assay was not implemented for clinical support. We conducted an integrated analysis of immunogenicity data pooled from two pivotal placebo-controlled trials to define the clinical impact of anti-etelcalcetide antibodies. While both pre-existing and developing anti-etelcalcetide antibodies were detected, we show here that they have no consequences for clinical exposure, efficacy, or safety of etelcalcetide.
新型治疗药物的免疫原性风险评估和生物分析策略应兼顾其独特的生物物理特性以及免疫原性的潜在后果。在评估钙敏感受体肽激动剂依特卡肽的免疫原性风险时，我们考虑了d -氨基酸“主链”和依特卡肽的生物转化可能使该药物充当半抗原的可能性。因此，我们验证并采用了一种表面等离子体共振免疫分析平台，该平台既有依特卡肽表面，也有依特卡肽 - “载体”表面，用于检测抗药物抗体（ADA）。尽管采用了多种免疫方法和基于细胞的灵敏活性测定法，但未检测到替代对照的体外中和活性证据。因此，未实施中和测定以支持临床研究。我们对两项关键的安慰剂对照试验汇总的免疫原性数据进行了综合分析，以确定抗依特卡肽抗体的临床影响。虽然检测到了预先存在的和正在产生的抗依特卡肽抗体，但我们在此表明，它们对依特卡肽的临床暴露、疗效或安全性没有影响。
